1. Technical Field
This invention relates to transdermal drug delivery.
2. Background Art
1. Monolithic Matrix Delivery Devices
Transdermal delivery has become an increasingly acceptable mode for administration of prescription and nonprescription drugs, and considerable effort has been expended toward development of transdermal drug delivery systems. A number of drugs have reached the market in transdermal delivery form, most popularly in the form of an adhesive patch.
Essentially, the methodology of transdermal drug delivery involves placing the drug on the skin surface and allowing the drug to permeate through the skin. Transdermal delivery devices employ a structure that serves as a reservoir for the drug and that provides for bringing the drug into diffusive communication with the skin surface. In one general type, the structure includes a three-dimensionally stable matrix material having a discrete size and shape; such a structure may be referred to as a "monolithic matrix".
A variety of monolithic matrix formulations have been proposed for use in transdermal delivery systems.
U.S. Pat. No. 5,149,538 describes transdermal delivery of opioids using an adhesive matrix prepared from polymers and copolymers of acrylic esters or methacrylic esters and copolymers of acrylic esters or methacrylic esters and other ethylenically-unsaturated monomers. Preferred acrylic adhesives are butyl acrylate, ethyl acrylate, ethyl hexyl acrylate, vinylacetate/ethylene acrylate and mixtures of these.
U.S. Pat. No. 4,956,171 describes using sucrose cocoate and methyl laurate for permeation enhancement in transdermal delivery of buprenorphine HCl or hydromorphone HCl, in an adhesive matrix made up of polyacrylic polymers or vinyl acetate-acrylic polymers, and, particularly, a vinyl acetate-acrylic multipolymer solution marketed by Montsanto Co. under the name Gelva.RTM. 788.
German Patent Publications DE 38 43 239 and DE 38 43 238 describe transdermal delivery of physostigmine using a polymer matrix made up, in one example, of an acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, and acrylic acid; a methacrylate copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid esters; and a triglyceride of capryl/caprinacids.
International Application No. PCT/US86/00789 (WO 86/06281) describes a pressure-sensitive adhesive tape for transdermal delivery of nitroglycerin, having a pressure-sensitive adhesive coating made up of an acrylic adhesive copolymer including as a major constituent a hydrophobic monomeric acrylic or methacrylic acid ester of a C.sub.4-10 alkyl alcohol; and including a reinforcing monomer selected from acrylic acid, methacrylic acid, C.sub.1-3 alkyl acrylate or methacrylate, acrylamide, methacrylamide, t-butyl acrylamide, diacetone acrylamide, vinyl ether, substituted ethylene, and vinyl ester.
European Patent Publication No. EP 0 481 443 A1 describes a transdermal delivery system having a polymeric matrix made up of a acrylic polymer 7927 79 Rohm-Pharma.
2. Ketorolac Tromethamine
Ketorolac is a pyrrolizine carboxylic acid derivative. Combined with tromethamine, ketorolac forms a salts ("ketorolac tromethamine"), which was greater aqueous solubility than ketorolac. The chemical structure of ketorolac and ketorolac tromethamine are shown below: ##STR1##
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug useful for short-term management of moderate to severe pain. Ketorolac tromethamine is available via prescription in oral tablet form (10 mg strength) and in intramuscular injection form (30 mg/ml).
Ketorolac tromethamine has a chiral center and is used as a racemate marketed under the name Toradol; the (-)-S isomer has many times greater analgesic potency than the (+)-R isomer (A. Guzman et al., 1986). Ketorolac tromethamine is an off-white crystalline powder and has a pK.sub.a value of 3.49. Ketorolac is quite lipophilic with a long PC (partition coefficient) value of 2.72 (Muchowski et al., 1985). Ketorolac tromethamine is extremely stable in aqueous solutions at pH 4-8, with a very long shelf-life at 25.degree. C. (L. Gu et al., 1988 a); however, it is light sensitive with decarboxylation, especially in the presence of oxygen (L. Gu et al., 1988 b), and ketorolac solutions should be protected from light exposure. The free acid of ketorolac in methanol exhibits UV absorption maxima at 245 nm and 312 nm, with molar absorptivities of 7080 and 17400, respectively (Franco et al. 1982).
Solubility of ketorolac tromethamine in various vehicle systems has been measured by Yu et al. (1988). Certain of the solubilities are given below.
______________________________________ Vehicles Solubilities (mg/ml) ______________________________________ water 725 propylene glycol (PG) 200 PG (50%), Oleic acid (50%) 110 ______________________________________
The analgesic property of ketorolac tromethamine, like that of other nonsteroidal anti-inflammatory drugs, appears to result from cyclo-oxygenase inhibition by way of action on inhibition of prostaglandin synthesis (Buckley et al. (1990)). Ketorolac tromethamine has high analgesic and anti-inflammatory potency; administered orally, the analgesic potency of ketorolac tromethamine is about 3-6 times that of indomethacin, about 25-50 times that of naproxen, and about 180 times that of aspririn, and the anti-inflammatory potency of ketorolac tromethamine is about 2-3 times that of indomethacin or naproxen.
Yu et al. (1988) describes percutaneous absorption of ketorolac and ketorolac tromethamine in Rhesus monkeys using a number of solution formulations. Two vehicle combinations (propylene glycol and linoleic acid, and propylene glycl and oleic acid) were shown to be effective in enhancing percutaneous absorption of both ketorolac and ketorolac tromethamine. High C.sub.max values were achieved within 8 hours.
3. Molsidomine
Molsidomine is a vasodilator, useful for example in treatment of angina pectoris.
Molsidomine (N-5-ethoxycarbonyl-3-morpholinosydnonimine) is a sydnonimine derivative having a mesoionic aromatic ring. It is also an ester prodrug. Its chemical structure is shown below: ##STR2##
Molsidomine is a white colorless crystal powder, practically tasteless or odorless. The imine has a molecular weight of 242 with a melting point of 140-141.degree. C. and a pK.sub.a value of 3.34 at 25.degree. C. It exhibits a UV absorption maximum at 326 nm in CHCl.sub.3. The solubilities (saturated) of molsidomine in various solvent systems, as reported in Yamada et al. (1987), Chem. Pharm. Bull., Vol. 35, pp. 3399-406, are shown below.
______________________________________ Vehicles Solubilities at 25.degree. C. (%) ______________________________________ Glycol salicylate 15.1 Propylene glycol 6.37 PEG 400 5.23 Glycerin 1.80 Oleic Acid 1.37 Octyl.decyl oil 0.36 Isopropyl myristate 0.09 ______________________________________
Molsidomine is shown to be freely soluble in CHCl.sub.3 ; soluble in dilute HCl, ethanol, ethyl acetate, methanol; sparingly soluble in water, acetone, benzene; very slightly soluble in ether, petroleum ether, Merck Index, 10.sup.th edition, page 892 (1983). It is soluble in propylene glycl and a variety of organic solvents. The chemical stability of molsidomine has been investigated in detail by Asahi et at. (1971), Chem. & Pharm. Bull., Vol. 19, pp. 1079-88, as shown below.
______________________________________ pH t.sub.90 (days) at 20.degree. C. ______________________________________ 1-2 38 4 250 5-7 950 (2.6 years) 10 400 11 40 ______________________________________
Molsidomine is photosensitive, particularly in sunlight.
Molsidomine has been shown to process a sustained anti-anginal effect and can be metabolized to SIN-1, which is readily converted into the active metabolite SIN-1A (carries a free nitroso group).
A very recent investigation on the vasodilation action of molsidomine and other vasodilators, including nitroglycerine reveals that it is the nitric oxide, liberated from the active metabolite SIN-1A, that activates the soluble guanylate cyclase, which in turn causes vasodilation. This is a major difference from the vasodilation action of nitroglycerin.
The coronary vasodilation action of nitroglycerine depends on the presence of cysteine. Cysteine deficiency was found to be associated with the tolerance developed for nitroglycerin uses. After prolonged exposure to nitroglycerin, tolerance toward the drug developed in coronary strips can be antagonized by cysteine. However, the active metabolite of molsidomine. SIN-1A, is active in both the presence and the absence of cysteine; therefore, molsidomine produces insignificant tolerance (Kulovetz et al. (1985), making it a better alternative for anti-anginal therapy.
In in vivo studies of transdermal delivery of molsidomine in rats, a combination of propylene glycol with 10% oleic acid produced an estimated flux of 399 .mu.g/hr-cm.sup.2 for molsidomine (Yamada et al. (1987) Chem. Pharm. Bull., Vol. 35(8), pp. 3390-98).
A single oral dose of 2 mg of molsidomine can produce anti-anginal effects in patients with coronary heart disease for 3 to 5 hours (J. Ostrowski et al. (1985) Am. Heart Jour., pp. 641-43). Different oral dosing levels can benefit patients having different degrees of coronary heart disease. Typically, oral doses of 2 mg three times daily, or 4 mg four times daily are suggested. Pharmacokinetic data indicate that the total clearance and peak plasma concentration of molsidomine were 46,000 ml/hr and 15 mg/ml, respectively, following administration of an oral dose of 2 mg. The bioavailability of molsidomine from oral doses is 44%. Generally, the effective blood concentration of a drug is less than the peak plasma concentration; therefore an estimation of target flux based on the effective blood concentration should be a better indication of the delivery rate required to produce therapeutic response.
European Patent Publication No. EP 0 127 468 A1 describes percutaneous formations containing various amounts of molsidomine and various absorption promoters.